Cancer (malignant neoplasm) is the number two killer of people in the U.S. Each year in the U.S. more than a million people are diagnosed with cancer and half of those will ultimately die from the disease. Cancer also afflicts many other living mammals.
Cancer occurs when normal living mammalian cells undergo neoplastic (malignant) transformation. Cancer is tenacious in its ability to uncontrollably metastasize throughout the mammalian body thus giving rise to a high mortality rate in many situations, particularly breast cancer.
Breast cancer is characterized by a high proliferative potential that can vary considerably from patient to patient. No vaccine or other universally successful method for the prevention or treatment of breast cancer is currently available. The rate of tumor cell proliferation has been shown in breast tumors to predict the response to radiation therapy and chemotherapy. Presently, measures of tumor cell proliferation are obtained by histological or flow-cytometric analysis. Both methods are limited by sampling procedures and unfortunately only about 60% to about 70% of patient samples are suitable for flow cytometric analysis.
It has been demonstrated that sigma-2 (σ2) receptors are expressed in high density in a number of human and rodent breast cancer cell lines (Cancer Research, 55, 408 (1995)). However, their expression in such cell lines is heterogenous, and their function is unknown.
Sigma (σ) receptors have also been identified as a distinct class of receptors that are expressed in liver, kidneys, endocrine glands, and in the central nervous system. Apart from the normal expression of sigma receptors in these tissues, several studies have reported their over expression in human and murine tumors (1-3). It has also been shown that there are two types of this receptor, σ1 and σ2 receptors. The σ2 receptor has been demonstrated to be a reliable biomarker for the proliferative status of solid tumors (2-4). Up regulation of σ2 receptors during proliferation was shown by selectively recruiting cells into quiescent and proliferative states and then measuring the receptor concentration (2-4). It was found that σ2 receptor concentrations increased tenfold when cells were recruited to proliferative states. Therefore, radioligands are desired that have both high affinity and high selectivity for σ2 receptors as tracers for the non-invasive assessment of the proliferative status of human solid tumors using noninvasive diagnostic imaging procedures such as PET and SPECT. To this end, a high affinity and highly selective σ2 radioligand is needed for the assessment of tumor status.
One of the major problems in the clinical management of breast cancer is the early detection and identification of an appropriate treatment strategy. A complication that has limited successful treatment is the inability to assess the proliferative status of breast tumors since breast cancer has a malignant potential that can vary considerably from patient to patient. The use of surrogate markers of proliferation such as the presence or absence of tumors in axillary lymph nodes suffers from a low sensitivity and specificity. Other methods such as determining the S-phase fraction of tumor biopsy or fine needle aspirates suffers from sampling problems associated with tumor heterogeneity that may not provide a true representation of the proliferative status of a solid tumor.
A recent strategy has focused on using noninvasive imaging procedures such as Positron Emission Tomography (PET) in order to assess the proliferative status of an entire tumor. This approach has relied primarily on the development of agents that target the increase in metabolic activity (i.e., [18F]FDG) or increased DNA (DNA precursors such as [11C]thymidine) or protein (i.e., [11C]methionine) synthesis associated with tumor proliferation. However, the majority of these agents have proven to be inadequate for providing an accurate measure of the proliferative status of solid tumors for a variety of reasons.
Cancer cure rates have increased dramatically over the years. This trend as a result of the widespread use of improved screening procedures that often lead to the early diagnosis/detection of cancer. However, as more selective treatment strategies have been developed, it is necessary to develop new and improved diagnostic procedures that can be used earlier to determine a potential treatment strategy based on the biological properties and proliferation of the tumor. In addition, it is desired to develop and have available non-invasive procedures that can provide the means for determining either a positive or negative response to a treatment strategy as early as possible thus extending the mammalian host's viability.
Additionally a continuing need exists for enhanced non-invasive methods that can accurately assess the proliferative status of breast cancer, as such methods could have a significant positive impact on determining an optimal therapy for treating human breast cancer patients.